Hindawi Publishing Corporation Advances in Urology Volume 2011, Article ID 256985, 7 pages doi:10.1155/2011/256985

Clinical Study Management of Bladder Cancer following Solid Organ Transplantation

Jeffrey J. Tomaszewski, Jeffrey A. Larson, Marc C. Smaldone, Matthew H. Hayn, and Stephen V. Jackman

Department of Urology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

Correspondence should be addressed to Jeffrey J. Tomaszewski, [email protected]

Received 16 July 2010; Revised 8 February 2011; Accepted 21 February 2011

Academic Editor: A. Stenzl

Copyright © 2011 Jeffrey J. Tomaszewski et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. Present our experience managing bladder cancer following liver and renal transplantation. Methods. Single institution retrospective review of patients diagnosed with bladder urothelial carcinoma (BUC) following solid organ transplantation between January 1992 and December 2007. Results. Of the 2,925 renal and 2,761 liver transplant recipients reviewed, we identified eleven patients (0.2%) following transplant diagnosed with BUC. Two patients with low grade T1 TCC were managed by TURBT. Three patients with CIS and one patient with T1 low grade BUC were treated by TURBT and adjuvant BCG. All four are alive and free of recurrence at a mean follow-up of 51 ± 22 months. One patient with T1 high grade BUC underwent radical and remains disease free with a follow-up of 98 months. Muscle invasive TCC was diagnosed in four patients at a median of 3.6 years following transplantation. Two patients are recurrence free at 24 and 36 months following radical cystectomy. and palliative XRT were performed in one patient with un-resectable disease. Conclusions. Bladder cancer is uncommon following renal and liver transplantation, but it can be managed successfully with local and/or extirpative therapy. The use of intravesical BCG is possible in select immunosuppressed patients.

1. Introduction database to identify patients diagnosed with bladder urothe- lial carcinoma (BUC) following renal and liver transplan- Renal and liver transplantation are the optimal treatments tation between January 1992 and December 2007. We for end-stage renal and liver disease [1, 2]. While the devel- examined demographic information including gender, age opment of bladder cancer following renal and liver trans- at transplant and cancer diagnosis, type of immunosuppres- plantation is quite rare [3], transplant recipients have an sion, smoking history, and time to cancer diagnosis. Tumor increased incidence of bladder cancer [4, 5], ranging from characteristics, including clinical and pathologic stage, mode 0.08% to 2.1% [6, 7], and frequently present with higher- of presentation, treatment (including adjuvant therapy and stage bladder cancer compared to the general population urinary tract reconstruction), and tumor progression were [5]. Optimal management of bladder cancer among renal also evaluated. Postoperative outcomes reviewed include and liver transplant recipients is not well defined. Most disease recurrence, allograft function following treatment, management strategies have only been briefly described in overall and cancer-specific survival, and length of followup. anecdotal case reports [8]andretrospectiveseries[7]. We present our single institution experience managing bladder No patient had a history of bladder cancer or hematuria cancer after renal and liver transplantation. prior to transplantation. Transurethral resection of bladder tumor (TURBT) with or without intravesical immunother- 2. Patients and Methods apy or chemotherapy (one patient received mitomycin-C) was used for treating nonmuscle-invasive tumors. Patients Through an Institutional Review Board approved protocol, were treated in accordance with the AUA guideline for we retrospectively reviewed our institutional transplant the management of nonmuscle invasive bladder cancer 2 Advances in Urology

(Hall MC, J Urol, 2007). BCG was used in select patients, (36–84) months. One patient with T1 high-grade BUC and and criteria for consideration of BCG included patients at a history of bilateral cutaneous ureterostomies (performed high risk for recurrence, large tumors, multifocal tumors, following transplantation for treatment of vesicoureteral fis- high-grade disease, or presence of CIS. Surgeon preference tula) underwent radical cystectomy and ureteroureterostomy also influenced the use of intravesical BCG, as multiple and remains disease-free with a followup of 98 months. None different urologists provided treatment to patients in the of the patients with T1 disease progressed to muscle invasive current series. BCG was administered as described by disease (Table 1). Lamm et al. Radical cystectomy with urinary diversion or Muscle invasive transitional cell carcinoma was diag- palliative external beam radiotherapy was used for those nosed in four patients at a median of 3.6 years (range 2 with muscle invasive disease. None of the patients with to 6 years) following transplantation (Table 2). Two patients muscle invasive disease received neoadjuvant or adjuvant underwent radical cystectomy with urinary diversion, one therapies. The radiation field was not significantly altered in with orthotopic neobladder, and one with percutaneous renal transplant patients, and immunosuppressive regimens allograft tube placement (due to significant remained unchanged in all patients. Patients were followed scar tissue and adhesions limiting small bowel mobilization postoperatively at regular intervals per established surveil- and creation of urinary diversion). Both patients remain lance protocols. recurrence-free at 24 and 36 months of followup, respec- tively. Ileal conduit urinary diversion and palliative radiation were performed in one patient with unresectable disease, 3. Results who subsequently died from disseminated intravascular coagulation 16 months following cancer diagnosis. One Of the 2,925 renal and 2,761 liver transplant recipients patient received palliative XRT and died of diffuse liver reviewed, we identified eight patients following and pulmonary metastases 12 months following treatment. transplant and three patients following liver transplant (n = Criteria for consideration of palliative XRT include evidence 11, 0.2%) who developed bladder cancer. The mean age of metastases at the time of diagnosis of muscle invasive BUC at transplantation was 62 ± 13 years (range 38–82 years) and unresectable disease. and all were male. Bladder cancer diagnosis was made at a mean interval of 39 ± 24 months (range 3.5–76 months) following transplantation. Mean age at the time of diagnosis 4. Discussion was 65 ± 12 years (range 44–83), and mean followup was 40 ± 27 months (range 12–98 months). Maintenance The increased risk for the development of malignancies immunotherapy protocols included tacrolimus + pred- following renal and liver transplant is well documented [9]. nisone, tacrolimus + mycophenolate mofetil + prednisone, Of special interest to urologists is the increased incidence tacrolimus + mycophenolate mofetil, and tacrolimus alone of genitourinary malignancies, including kidney and bladder in 54.5%, 27.3%, 9.1%, and 9.1% of patients, respectively. cancer, following transplantation [10]. Transplant recipients It was not necessary to alter immunotherapy protocols are up to 3.3-times more likely to develop BUC than the gen- following diagnosis or in the treatment of BUC. There were eral population [4]. More alarmingly, recent data also suggest no deleterious effects on graft survival or function following that renal transplant recipients and patients with end-stage urologic intervention. Prior to urologic intervention, mean renal disease present with higher-stage [5], biologically more serum creatinine was 1.4 mg/dL (range 0.9–2.0 mg/dL). At aggressive tumors [11] and experience worse outcomes than last followup, serum electrolyte levels were normal, and the general population [11]. The etiology of increased risk for mean serum creatinine level was 1.5 ± 0.4 mg/dL (range 1.0– BUC among transplant recipients is multifactorial [5], and in 2.1 mg/dL). Liver function tests were not affected by urologic addition to common risk factors for BUC such as smoking, intervention. also includes risk factors unique to the transplant recipient, Ten patients presented with gross hematuria, and one such as direct cytotoxic damage from immunosuppressive patient was diagnosed incidentally by cross-sectional imag- agents [12], impaired DNA repair mechanisms in immuno- ing. Imaging studies performed at the time of diagnosis compromised patients [13], impaired protection against viral revealed no evidence of lymphadenopathy, metastasis, or oncogenes [14], and urinary tract infections [15]. upper tract urothelial carcinoma. Two patients with low- The incidence of de novo BUC following renal and liver grade T1 BUC were managed by transurethral resection transplantation in our series is 0.27% and 0.11%, respec- (TURBT) alone. Three patients with CIS and one patient tively, and is comparable to other series. The University with T1 BUC were treated by TURBT and adjuvant intrav- of California, San Francisco, reported the development of esical bacille Calmette-Guerin (BCG) immunotherapy. The de novo BUC in 0.08% of over 6000 renal transplant patient with T1 disease recurred locally after 7 months recipients [7] while The University of Wisconsin reported and was treated with a repeat course of BCG. Two of the a 0.19% incidence of BUC after renal transplantation [4]. patients with CIS recurred at 18 and 12 months: the first The United Network for Organ Sharing (UNOS) database was managed with repeat TURBT and a 6-week course of (1986 to 2001) reported a similarly low prevalence (0.024%) Mitomycin C; the second received another 6-week course of post-transplantation BUC [7]. Conversely, Kamal et al. of BCG. All four patients treated with BCG are alive and [3] reported a higher rate (0.37%) of BUC following renal free of further recurrence at a mean followup of 51 ± 22 transplantation in Egypt than observed in the present cohort. Advances in Urology 3

Table 1: Characteristics of patients with nonmuscle-invasive TCC of the bladder.

Patientnumber1,23456 7 Ageattransplant667782666345 Type of transplant Liver Renal Renal Renal Liver Renal Age at diagnosis 66 79 83 72 65 47 Immunosuppression FK, MMF, Pred FK, Pred FK FK, MMF FK, Pred FK, Pred Clinical stage T1NxMx T1NxMx TisNxMx TisNxMx TisNxMx T1N0Mx Histology TCC TCC CIS CIS CIS TCC Grade Low Low High High High High Treatment TURBT TURBT TURBT TURBT TURBT Cystectomy, ureteroureterostomy Adjuvant therapy None BCG BCG BCG BCG Mitomycin C Followup (months) 28, 24 40 36 84 42 98 Recurrence None Local Local None Local None FK: tacrolimus; MMF: mycophenolate mofetil; Pred: prednisone; CIS: carcinoma in site; TURBT: transurethral resection bladder tumor; BCG: bacille- Calmette Guerin.

Table 2: Characteristics of patients with muscle-invasive TCC of the bladder.

Patient number 1 2 3 4 Ageattransplant 38 58 60 66 Type of transplant Renal Liver Renal Renal Age at diagnosis 44 60 63 70 Immunosuppression FK,Pred FK,MMF,Pred FK,Pred FK,Pred Pathologic stage T3aN0M0 T3N2M0 T2N0M0 T2N0M1 Histology TCC, CIS TCC TCC TCC Grade High High High High Treatment Cystectomy, allograft nephrostomy Cystectomy, neobladder Palliative XRT, Ileal conduit Palliative XRT Followup (months) 24 36 16 12 Metastasis(months) None None None Liver,pulmonary(12) Status Alive Alive Deceased (DIC) Deceased FK: tacrolimus; MMF: mycophenolate mofetil; Pred: prednisone; CIS: carcinoma in site; TURBT: transurethral resection of bladder tumor; DIC: disseminated intravascular coagulation; XRT: external beam radiotherapy.

The authors accounted for this discrepancy by the high cancer outcomes [11]. While most primary diagnoses of prevalence of bilharzial infestation among the Egyptian BUC in the general population are low-grade superficial population; and there was evidence of bilharzial cystitis in disease [16], a majority of our cohort presented with high five of the seven cases reported by Kamal et al. [3]. grade disease, and muscle invasion and nodal metastases As a result of perioperative and induction immuno- were noted in 4 and 2 patients, respectively. Although suppressive therapy used in the immediate posttransplant recent data have demonstrated favorable outcomes utilizing period, transplant recipients experience the greatest risk neoadjuvant chemotherapy in patients with muscle-invasive of developing bladder cancer within the first 6 years bladder cancer, the patients in the current series were after transplantation [11]. Numerous reports document treated prior to the widespread utilization and acceptance the rapidly progressive nature of bladder cancer in the of neoadjuvant chemotherapy [17]. Neoadjuvant cisplatin transplant population [7, 8]. Comparison of transplant can be considered in solid organ transplant recipients recipients from the Israel Penn International Transplant [18], but no specific selection criteria exist as data remain Tumor Registry to adults in the general population (from limited; its use should be approached with the same caution the Surveillance, Epidemiology, and End Results database) one would use administering adjuvant chemotherapy to revealed a more advanced cancer stage at diagnosis in trans- immunosuppressed transplant recipients. However, reason- plant recipients as well as a worse stage-stratified disease- able cancer-specific survival was achieved after aggressive specific survival [11]. Immunosuppressive therapy alters the therapy. The survival rates of 90% (pTxNxMx) and 50% host-tumor relationship by inhibition of IL-2 stimulated (≥pT2) at a mean followup of 40 ± 27 months in T-cell proliferation, enhancement of tumor angiogenesis, our cohort are comparable to the 5-year overall survival and a dose-dependent reduction in DNA repair capability, observed in large series following cystectomy in nontrans- resulting in increased biologic aggressiveness, and likely plant patients with pT2 and pT3a BUC (77% and 58%, explains why transplantation confers a poor prognosis for resp.) [19]. Our findings suggest that early and aggressive 4 Advances in Urology screening should be considered in transplant recipients been questioned. However systemic immunosuppression [5, 11]. may not always induce a local immunosuppressive effect, and To our knowledge, there are no published recommenda- therefore the bladder immunologic-inflammatory reaction tions for the management of immunosuppression after sur- obtained with BCG may maintain its efficacy [27, 37]. gical resection of BUC. However, some have suggested While Buzzeo et al. [4] refrained from using BCG in that for patients with localized disease, no alteration in immunosuppressed patients, Palou et al. [27]reportedsafe immunosuppression is required [20]. The experience with administration of intravesical BCG in 3 renal transplant adjuvant cisplatin-based chemotherapy in renal transplant recipients. It should be noted that while there were no recipients is limited, but it has been used in those with adverse reactions to BCG, all 3 patients were treated well functioning and poorly functioning allografts [7, 21]. with prophylactic isoniazid and rifampin [27]. The safe Dose increase and the side effect profile are adversely affected administration of intravesical BCG without concomitant because most immunosuppressive medications have sys- antituberculin prophylaxis has also been reported in 3 temic effects such as nephrotoxicity (cyclosporine) or bone immunosuppressed renal transplant recipients [3, 28]. In marrow suppression (cyclophosphamide, mycophenolate) the present study, we demonstrate the safe and efficacious [7]. However, decrease of immunosuppressive medications administration of adjuvant intravesical BCG therapy in 4 is possible without rejection since the chemotherapeutic immunosuppressed transplant recipients. Caution is advised cytotoxic agents are themselves immunosuppressive and prior to administration of intravesical therapy, as mortality may prevent allograft rejection [7]. Some have argued that due to general visceral deficiency has been reported in a cyclosporine itself increases the risk of malignancy compared transplant recipient following BCG treatment [38]. Given to other immunosuppressive medications and, therefore, the limited data regarding the safety of intravesical BCG should not be part of standard regimens [7]. Additional data in immunosuppressed patients, we advocate its use only in are needed to support this concept. The risks of continued select patients while maintaining a high degree of clinical immunosuppression merely to preserve the allograft when suspicion for sepsis and administration of prophylactic faced with a known, aggressive malignancy are unclear and antibiotics on a case by case basis. Ciprofloxacin was used deserve investigation [7]. in a single dose before each BCG treatment in 80% of our Hematuria was the main presenting symptom in the cur- patients. rent study. While hematuria in renal transplant recipients For patients with muscle-invasive disease, radical cys- can have several etiologies, it requires thorough evaluation tectomy offers the best chance at cure and is technically with urinalysis and culture, upper urinary tract imaging, feasible in kidney and liver transplant recipients [7, 22]. and [22]. Urinary cytology is reliable and has a Reported outcomes of radical cystectomy in renal transplant significantly low false-positive rate in renal transplant recip- recipients are summarized in Table 3. It deserves mention ients [23]. Newer diagnostic modalities such as fluorescent that the rate of muscle invasive BUC observed in our in-situ hybridization and tumor markers have not been cohort (36%) was higher than that typically seen in the evaluated in the transplant population [22]. While previously general population. Although immunosuppressed transplant reported data have demonstrated an increased incidence patients may be at higher risk to develop more aggressive (66.6%) of upper tract BUC in small series of renal transplant disease, the current series is too small to draw definitive recipients with bladder tumors [24], no upper tract disease conclusions. Prolonged survival and graft preservation have was identified in our cohort. Interestingly, none of the been demonstrated after radical cystectomy in transplant 11 patients who developed BUC had a previous smoking recipients [3, 7]. Reconstructive options range from uri- history, a well-recognized risk factor for the development of nary diversion with incontinent (ileal conduit, cutaneous BUC. , nephrostomy) or continent urinary diversions The optimum management and clinical outcomes of (ileal neobladder). Ileal conduit urinary diversion, which bladder cancer in renal and liver transplant recipients reduces exposure of urine to the absorptive bowel mucosa, are not well defined, and treatment is dependent upon should be used in patients with significant renal dysfunction disease stage [22]. For patients with Ta or T1 low-grade [22], while orthotopic substitution is feasible in patients with disease, TURBT may be both diagnostic and therapeutic. a creatinine clearance of >40 mL/min [3, 7, 25]. Radical The use of adjuvant intravesical therapies such as BCG cystectomy should be performed in appropriate situations, and Mitomycin C should be considered for patients at and in some patients with advanced disease, cystectomy may high risk for recurrence (large tumors, multifocal tumors, not be feasible. One patient in the cohort underwent pallia- high-grade disease, or presence of CIS) [22]. While BCG tive radiation and ileal conduit urinary diversion following hasbeenshowntobemoreeffective than Mitomycin C aborted cystectomy, for the purpose of providing local to prevent recurrence and disease progression [36], its symptom control. Radical cystectomy with urinary diversion use in immunocompromised patients has been cautioned did not impact on graft function or survival in the current [4, 37]. BCG is a live attenuated strain of Mycobacterium cohort. bovis that acts as a recall antigen and evokes a nonspecific Given the high incidence (up to 41%) [26]ofsynchro- immune response [3], which carries the risk (1 in 12,500 nous upper tract TCC in renal transplant recipients, some patients) of severe tuberculous reaction, sepsis, and death advocate that prophylactic bilateral native nephroureterec- among immunosuppressed patients [4, 37]. The efficacy of tomies be performed at the time of cystectomy [7, 26]. Lang intravesical BCG in immunosuppressed patients has also et al. [25], conversely, found no evidence of upper tract TCC Advances in Urology 5

Table 3: Summarized data on all cases of radical cystectomy and urinary diversion performed for postrenal transplant bladder cancer [3].

Number of Followup Study radical Type of urinary diversion (n) Oncologic outcome (n) Graft function (n) (months) Neobladder (1) Present 3 Allograft nephrostomy (1) 24–98 NED (3) Stable (3) Cutaneous ureterostomies (1) NED (3) Kamal et al. [3] 5 Neobladder (5) 3–24 Stable (5) Mets (2) Stable (3) NED (3) Lang et al. [25] 4 Neobladder (4) 11–118 Chronic allograft Local recurrence (1) nephropathy (1) NED (1) Neobladder (2) Master et al. [7]3 10–105 Ureteric recurrence (1) Stable (3) IC (1) Paravaginal recurrence (1) NED (3) Kao et al. [26]4IC(4)4–39 Unknown Mets (1) Palou et al. [27] 1 IC (1) 10 NED (1) Stable (1) Wang et al. [28]0 Giessing et al. [29] 1 Neobladder (1) 20 NED (1) Stable (1) Perabo and 1 Neobladder (1) 8 NED (1) Stable (1) Schultze-Seemann [30] Colombo et al. [31] 1 Neobladder (1) 8 NED (1) Stable (1) Schmidt et al. [32] 1 Unknown Unknown Unknown Unknown Lam et al. [33] 1 IC (1) Unknown Unknown Unknown Lemmers and Barry [34] 2 IC (2) 6–24 NED (2) Stable (2) Tuttle et al. [35] 1 IC (1) 14 NED (1) Stable (2) NED, no evidence of disease; IC, ileal conduit; Mets, metastases.

in 75% of patients undergoing prophylactic nephroureterec- suggests that these tumors were not present prior to trans- tomy. Prophylactic nephroureterectomy was not performed plantation. in the current cohort, and followup studies to date reveal no evidence of metachronous upper tract disease. The 5. Conclusions allograft is rarely the source of BUC and in the vast majority of cases can be preserved [24]. Given the morbidity of We report encouraging oncologic outcomes in eleven pa- nephroureterectomy in this complex population, we agree tients undergoing definitive therapy without compromising that prophylactic nephroureterectomy should be reserved allograft function. The use of intravesical BCG is possible in for patients with high-risk features, such as documented select immunosuppressed patients with CIS or nonmuscle- multifocal disease and CIS. invasive disease. Aggressive extirpative and urinary The current study is limited by sample size and retro- diversion is technically feasible and should be considered in spective design. Reporting bias may have also occurred in the transplant recipients with muscle invasive BUC and a good early years of the study, prior to effective data acquisition. performance status. Additionally, although all patients were screened for bladder cancer prior to renal transplant, we cannot exclude the Conflict of Interests presence of a pre-existing tumor. Given the short preclinical latency of BUC [39], however, pre-existing tumors would The authors declare that they have no conflict of interests to likely have been detected at the time of ureteral stent report. removal in the early post-operative period. Therefore, given the short preclinical latency period and the thorough pre- transplant evaluation, factors associated with transplantation References more likely contributed to tumorigenesis as opposed to [1]A.J.Matas,W.D.Payne,D.E.R.Sutherlandetal.,“2,500 increased surveillance in renal and liver transplant recipients. living donor kidney transplants: a single-center experience,” Additionally, the mean duration from renal transplant to Annals of Surgery, vol. 234, no. 2, pp. 149–164, 2001. diagnosis of bladder cancer was 3.3 years, and such a long [2] I. Penn, “Posttransplant malignancies,” Transplantation Pro- period between renal transplantation and BUC development ceedings, vol. 31, no. 1-2, pp. 1260–1262, 1999. 6 Advances in Urology

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